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PubMed2006

Radiofrequency in the treatment of craniofacial plexiform neurofibromatosis: a pilot study.

BACKGROUND: Neurofibromatosis type 1 manifests itself by the development of plexiform neurofibromas, with craniofacial deformities caused by bone alterations and soft-tissue infiltration. The medical treatment of this disease is disappointing, and the surgical management of these deformities calls for aggressive procedures. There is a strong risk of recurrence. METHODS: A pilot study was performed to test radiofrequency as a minimally invasive method with which to diminish the size of craniofacial neurofibromas either as an adjunct to craniofacial surgery (in cranio-orbital neurofibromas) or to avoid a visible scar in young patients (in infraorbital neurofibromas). Five patients ranging in age from 6 to 18 years were treated by three procedures 2 months apart using radiofrequency performed under local anesthesia or under sedation for the youngest patients. RESULTS: The tolerance of the treatment was excellent, with no major side effects and no pain in the postoperative course. A diminution of the size of the lesion was noted clinically in four patients and on computed tomography in two patients. A biopsy performed in one case illustrated the effect of the treatment. CONCLUSIONS: A partial diminution or stabilization of plexiform neurofibromas may be obtained using radiofrequency. This treatment is well tolerated. The best effect can be observed in the early stages of the disease. The optimal dose and frequency of the procedure require further study.

Adolescent↗
PubMed1997

Hereditary spinal neurofibromatosis: a rare form of NF1?

We describe a family in which seven members in three generations were affected with a rare spinal neurofibromatosis. The affected adults showed, at the ages of 32, 37, 38, and 61, respectively, multiple spinal neurofibromas symmetrically affecting all spinal roots. Two patients were operated on for histopathologically proven cervical spinal neurofibromas. All patients had café au lait spots, one had several freckles in the axillary area, and two had possible dermal neurofibromas, but iris Lisch-nodules were not present. Other signs of neurofibromatosis types 1 and 2 were absent. A linkage study of the family suggested close linkage to the NF1 locus and excluded it from the NF2 locus. The DNA analysis of histopathologically verified spinal neurofibromas in two patients showed no evidence of LOH at 17q11.2. The findings in the present family, together with those in a family previously described, suggest a clinically distinct form of neurofibromatosis with extensive spinal neurofibromas and café au lait macules, which may be allelic to the NF1 gene.

Adult↗
PubMed2003

Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.

Animals↗
PubMed1990

Mitogen accumulation in von Recklinghausen neurofibromatosis.

Most, but not all, patients with von Recklinghausen neurofibromatosis develop tumors (neurofibromas) that contain large numbers of Schwann cells and fibroblasts. To begin to understand the molecular events that contribute to cell proliferation in these benign tumors, we have analyzed extracts of neurofibromas to determine whether they contain mitogens for Schwann cells or fibroblasts, or both. Schwann cell and fibroblast mitogens are present in neurofibroma extracts. All the neurofibromas analyzed contain a Schwann cell mitogen similar to a neuronal cell surface molecule known to stimulate Schwann cell proliferation during normal development; this mitogen also stimulates fibroblast proliferation. Basic fibroblast growth factor is present in 60% of tumors evaluated. Accumulation of mitogenic substances may contribute to the growth of neurofibromas.

Cell Division↗
PubMed2003

Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers.

Neurofibromatosis type 1 (NF1), an autosomal dominantly-inherited disorder, is mainly characterized by the occurrence of multiple dermal neurofibromas and is caused by mutations in the NF1 gene, a tumor suppressor gene. The variable expressivity of the disease and the lack of a genotype/phenotype correlation prevents any prediction of patient outcome and points to the action of genetic factors in addition to stochastic factors modifying the severity of the disease. The analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients revealed that each neurofibroma results from an individual second hit mutation, indicating that factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. A mutational screen of numerous neurofibromas from two NF1 patients presented here revealed a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations are reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, our results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease.

Adult↗
PubMed2004

The impact of PET scanning on management of paediatric oncology patients.

PURPOSE: Limited information is available on the use of positron emission tomography (PET) in paediatric oncology. The aim of this study was to review the impact of PET on the management of paediatric patients scanned over a 10-year period. METHODS: One hundred and sixty-five consecutive oncology patients aged 11 months to 17 years were included. Two hundred and thirty-seven scans were performed. Diagnoses included lymphoma (60 patients), central nervous system (CNS) tumour (59), sarcoma (19), plexiform neurofibroma with suspected malignant change (13) and other tumours (14). A questionnaire was sent to the referring clinician to determine whether the PET scan had altered management and whether overall the PET scan was thought to be helpful. RESULTS: One hundred and eighty-nine (80%) questionnaires for 126 patients were returned (63 relating to lymphoma, 62 to CNS tumours, 30 to sarcoma, 16 to plexiform neurofibroma and 18 to other tumours). PET changed disease management in 46 (24%) cases and was helpful in 141 (75%) cases. PET findings were verified by histology, clinical follow-up or other investigations in 141 cases (75%). The returned questionnaires indicated that PET had led to a management change in 20 (32%) lymphoma cases, nine (15%) CNS tumours, four (13%) sarcomas, nine (56%) plexiform neurofibromas and four (22%) cases of other tumours. PET was thought to be helpful in 47 (75%) lymphoma cases, 48 (77%) CNS tumours, 24 (80%) sarcomas, 11 (69%) neurofibromas and 11 (61%) cases of other tumours. PET findings were verified in 44 (70%) lymphoma cases, 53 (85%) CNS tumours, 21 (70%) sarcomas, 12 (75%) neurofibromas and 11 (61%) other tumour cases. CONCLUSION: PET imaging of children with cancer is accurate and practical. PET alters management and is deemed helpful (with or without management change) in a significant number of patients, and the results are comparable with the figures published for the adult oncology population.

Adolescent↗
PubMed1987

Neuronal growth factors from tumours of Von Recklinghausen neurofibromatosis.

Explants of 21 neurofibromas from 16 patients with Von Recklinghausen neurofibromatosis (NF-I) plus tumour tissue from 5 comparison patients and normal tissue from one of the NF-I patients were assayed for neuronal growth factor(s) using dissociated embryonic sensory neurons from chick embryo. Twenty-one of 21 neurofibroma explants released detectable quantities of neuronal growth factors, but only 2 of 8 non-neurofibroma tissue explants released activity. While antiserum to mouse nerve growth factor (NGF) fractionally inhibited neurite outgrowth induced by some of the neurofibromas, overall differences between assays containing antibody and controls reached statistical significance in 3 cases; in one case, explants of a separate tumour from the same patient had no detectable NGF-like activity. These data support the hypothesis that local release of neuronal growth factors in neurofibromas are responsible for neurites observed within these tumours. Further evidence that endoneurial tissue of peripheral nerve is a rich source of heterogeneous neuronal growth facts has been provided by these studies.

Axons↗
PubMed2005

Peripheral and cranial nerve sheath tumors.

PURPOSE OF REVIEW: The intention of the authors is to provide the reader with an overview of the recent advances in the diagnosis and treatment of nerve sheath tumors. Vestibular schwannomas, neurogenetic syndromes such as schwannomatosis and multiple isolated neurofibromas, and malignant peripheral nerve sheath tumors are covered in this review. RECENT FINDINGS: Over the last year, literature focusing on different management strategies for patients with vestibular schwannomas dominated the field. Surgical options for this group of patients are changing. Stereotactic radiation is also employed more frequently with promising results. New insights into the biology of peripheral nerve tumor development and growth, including expression of vascular endothelial growth factor by vestibular schwannomas and the role of Notch signaling in malignant transformation of benign neurofibromas have been described. Diagnostic criteria for schwannomatosis, a recently described condition, are being developed. Several cases of multiple isolated neurofibromas and spinal neurofibromas were reported. SUMMARY: Peripheral nerve tumors are classified according to the specific features of cellular differentiation. The most common types include schwannoma and neurofibroma. These tumors can occur sporadically or as manifestations of genetic syndromes such as neurofibromatosis types 1 and 2 or schwannomatosis. The majority of peripheral nerve tumors are benign but malignant transformation does occur. Metastatic tumors can also affect peripheral nerves. The diagnostic modality of choice is magnetic resonance imaging. Positron emission tomography is a useful technique in the presurgical differentiation between benign and malignant peripheral nerve sheath tumors. Treatment is directed towards symptomatic control. Surgery, radiation and, in rare instances, chemotherapy are the major treatment modalities employed.

Cranial Nerve Neoplasms↗
PubMed2005

Clinicopathological study of neurofibromatosis type 1: an experience in Nigeria.

BACKGROUND: Neurofibromatosis type 1 (NF1) is the commonest single gene autosomal dominant disorder, and its diagnosis is usually composed of a set of clinical criteria. Histological examination of skin lesions is often neglected. This study was designed to evaluate the clinical and pathologic pattern of NF1 among Nigerians and to emphasize the place of histological examination. METHODS: A retrospective case study of 98 clinically diagnosed NF1 patients whose dermal mass lesions (neurofibromas) were excised and processed for histological diagnosis over a period of 22 years (1980-2001) at the University of Ilorin Teaching Hospital (UITH), Ilorin, Nigeria. RESULTS: There were 98 patients: 60 males and 38 females (ratio 3 : 2) aged 1-99 (mean +/- S.D. = 3.4 +/- 1.7) years. All patients had neurofibromas, which were benign in 95 patients (96.9%) and malignant in three (3.1%) patients, while 94 (96%) patients had cafe-au-lait spots. Benign neurofibromas were clinically cutaneous [50 (51%)], subcutaneous [37 (37.8%)] and plexiform [8 (8.2%)]. Site distribution of the neurofibromas included the extremities (50%), trunk (20.4%), head and neck (19.4%), and multiple sites (10.2%). Three patients presenting with neurofibosarcomas were aged 4, 23 and 27 years, respectively. Their deaths were responsible for the mortality rate of 3.1% recorded in this study. CONCLUSIONS: In our setting, NF1 is more common among males, with the highest density of neurofibromas covering the extremities.

Adolescent↗
PubMed2007

Microarray-based identification of tenascin C and tenascin XB, genes possibly involved in tumorigenesis associated with neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical manifestations. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors, which are resistant to conventional therapies. EXPERIMENTAL DESIGN: To identify new signaling pathways involved in the malignant transformation of plexiform neurofibromas, we applied a 22,000-oligonucleotide microarray approach to a series of plexiform neurofibromas and malignant peripheral nerve sheath tumors. Changes in the expression of selected genes were then confirmed by real-time quantitative reverse transcription-PCR. RESULTS: We identified two tenascin gene family members that were significantly deregulated in both human NF1-associated tumors and NF1-deficient primary cells: Tenascin C (TNC) was up-regulated whereas tenascin XB (TNXB) was down-regulated during tumor progression. TNC activation is mainly due to the up-regulation of large TNC splice variants. Immunohistochemical studies showed that TNC transcripts are translated into TNC protein in TNC-overexpressing tumors. Aberrant transcriptional activation of TNC seems to be principally mediated by activator protein transcription factor complexes. CONCLUSION: TNXB and TNC may be involved in the malignant transformation of plexiform neurofibromas. Anti-TNC antibodies, already used successfully in clinical trials to treat malignant human gliomas, may be an appropriate new therapeutic strategy for NF1.

Alternative Splicing↗
PubMed1998

CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions.

OBJECTIVE: The authors examined the incidence and radiologic characteristics of plexiform neurofibromas in neurofibromatosis-1 (NF-1) to define a cohort at greatest risk for malignant nerve-sheath tumors. BACKGROUND: Plexiform neurofibromas are a frequent complication of NF-1. They can impair function, produce disfigurement, and be the site for the development of malignant nerve-sheath tumors. The incidence and natural history of plexiform neurofibromas is unknown. METHODS: CT imaging of the chest, abdomen, and pelvis was performed in 91 of 125 consecutive adults (age, > or = 16 years) with NF-1. RESULTS: Twenty percent of patients had plexiform neurofibromas of the chest in the paraspinal, mediastinal, or supraclavicular area. Approximately 40% of patients had abnormal abdominal/pelvic scans. The paraspinal, sacral plexus, sciatic notch, and perirectal regions were the most common sites. Most plexiform neurofibromas were asymptomatic. Imaging also revealed a number of tumors, including malignant nerve-sheath tumors, adrenal tumors, carcinoids, and schwannomas. CONCLUSIONS: The frequency of plexiform lesions and other tumors in NF-1 indicates that clinicians should monitor young adults carefully; however, imaging characteristics alone cannot reliably distinguish benign from malignant lesions.

Abdominal Neoplasms↗
PubMed2001

[Neurofibromatosis (NF1) and neuroleprosy: immunoreaction against pathologic Schwann-cells. Physiopathogenetic observations].

BACKGROUND: We reviewed the literature evaluating the immune reaction in neurofibromatosis (NF1) and neuroleprosy, so as to underline the immunopathegenetic parallelism and the possible therapeutic implications regarding the treatment of these two disorders. In particular we evaluated the systemic modifications and the local fibrotic events that lead to nerve damage in NF1 and complete neuronal destruction as in leprosy. METHODS: With the above aim in mind we studied the histology, histochemistry and immunohistochemistry (Schwann cells and immunoglobulins) of four plexiform neurofibroma, one common neurofibroma and one case of borderline neuroleprosy (BT). RESULTS: Two plexiform neurofibromas showed an evident immune reaction that was antibody mediated with numerous IgG; the remaining neurofibromas represented other stages of disease evolution and disease quiescence and thus showed a scarce immune reaction with a reduced presence of immunoglobulins. All the neurofibromas showed the presence of fibrous bundles. In the case of neuroleprosy (BT), the immune reaction was modest, immunoglobulins were present and fibrotic transformation on neuronal fibers was observed. CONCLUSIONS: Being that pathologic Schwann cell are the site of immune reactions that can become abnormal (at times with autoimmune reactions), clinical as well as biochemical surveillance of leprous neuropathy and NF1 could allow for a timely modification of the abnormal reaction with selective immunomodulators. The inactivation of the mycobacterial RNA polymerase or of the NF1 gene could offer hope for controlling disease activity and disease evolution of the two disorders.

Adolescent↗
PubMed1981

Cutaneous manifestation of neurofibromatosis: cellular interaction, pigmentation, and mast cells.

The patchy, mosaic nature of the hyperpigmentation defect in neurofibromatosis (NF) is shown to be compatible with a cell-cell interaction model involving at least 2, and perhaps 3 cell types. Two approaches to analysis of the cellular interaction model are outlined in detail: 1) Demonstration of the more or less random number, size, and distribution of café-au-lait spots (CLS); 2) Documentation of topographic features of hyperpigmentation and neurofibroma skin lesions with special significance, including: a) Localized, intense pruritus coincident with developing or numerous neurofibromas, responding to treatment with antihistamines or oral disodium cromoglycate (the mast cell is suggested as a mediator of the pruritus and perhaps of neurofibroma development); b) The high frequency of areolar neurofibromas in postpubertal NF females, suggesting a localized estrogenic effect on neurofibroma development; c) The recognition that the usual NF freckling (eg axillary) is essentially restricted to intertriginous zones and that they therefore probably have a different mechanism of origin than do CLS.

Cell Communication↗
PubMedDate not supplied

[Von Recklinghausen's disease: experimental models and comparative aspects].

Von Recklinghausen's disease, or neurofibromatosis type 1 (NF-1), is an autosomal dominant syndrome with a highly variable tumorous (neurofibromas, gliomas, Wilms' tumors, leukemia, pheochromocytomas) and non-tumorous (cafe-au-lait skin spots, iris and ciliar hamartomas, osseous lesions) manifestations. NF-1 gene is mapped to chromosome 17. Central or bilateral acoustic neurofibromatosis (NF-2) has a gene mapped to chromosome 22. Hereditary and sporadic NF-1 are recognized. The most typical manifestation of NF-1-skin neurofibroma--has has a characteristic plexiform structure. Spectrum of tumors (schwannomas, gliomas, Wilms' tumors) produced by transplacental treatment with strong environmental mutagens-carcinogens-ethylnitroso- and methylnitrosourea (ENU and MNU, respectively) resembles on the whole that observed in human sporadic NF-1. Location of neurofibromas depends on the species: skin and subcutaneous tissue in humans, cattle and hamsters, trigeminal nerve, spinal roots in rats. Rat schwannomas differ from human neurofibromas by malignant structure, frequently with cystic component, but if induced by ENU treatment at day 15 of the pregnancy they resemble human plexiform neurofibromas with intraneural and extraneural growth of tumor cells. There were attempts to reproduce a transgenerational transmission of ENU carcinogenic effect, i.e. hereditary form of NF-1. In the experiments of this type the offsprings of rats prenatally treated with ENU remained untreated. The incidence of PNS, CNS and Wilms' tumors in these untreated offsprings in some experiments was significantly higher than in controls thus confirming the possibility, in principle, of hereditary NF-1 modelling. Only 10% of tumors developing in such untreated descendants of ENU treated parents contained a specific mutation of neu oncogene compared to 90-100% in tumors arising following direct treatment with ENU. The mechanisms of the transgenerational carcinogenesis are discussed. Lesions imitating NF-1 and in part NF-2 in transgenic mice with an HTLV-1-tax gene as well as in p-53 knockout mice are mentioned.

Animals↗
PubMed1997

Cervical neuromas with extradural components: surgical management in a series of 57 patients.

OBJECTIVE: Cervical neuromas with extradural components (intraextradural or strictly extradural forms) are rare. Their resection raises the problems of nerve root preservation, vertebral artery (VA) control, and spinal stability. METHODS: A series of 57 patients with neuromas (29 neurofibromas, 23 schwannomas, 4 neurofibrosarcomas, and 1 plexiform neurofibroma) was treated during the period of 1980 to 1995, using one of the lateral approaches (antero- or posterolateral approach). The VA was always controlled before resection of the tumor. In cases of intraextradural forms, the intradural component was removed by a complementary laminectomy (three patients) in the early period and then by an oblique corpectomy through the same lateral approach (five patients) in the late period. A laminectomy had been performed in 15 other patients (11 patients with intraextradural neuromas) before they were referred to us. These patients included seven with recurrent neuromas, occurring after an average period of 4.1 years (1-9 yr). RESULTS: Complete resection was achieved in all except two patients, in whom the nerve root reacted positively to intraoperative stimulation and could not be separated from the tumor. One of the patients was subsequently operated on after 2 years. Another recurrence was observed in another patient at 1 year. The four patients with sarcomas died from recurrence within 2 years. The rate of root preservation included an average of 28%, including 43.5% for schwannomas, 18% for neurofibromas, 44% for lower cervical neuromas (C4-C8), and 4.5% for upper cervical neuromas (C1-C3). Worsening of preoperative neurological deficits was observed in only two patients. The VA was always preserved, except in one patient with a sarcoma that was preoperatively occluded. No instability was observed in any of the patients. CONCLUSION: Complete resection with good neurological results can be achieved in most patients harboring cervical neuromas each with an extradural component by using a lateral approach and VA control. If the root cannot be separated from the tumor, especially in patients with neurofibromas, intraoperative stimulation can help decide whether the root may be divided without incurring postoperative deficit. The lateral approach permits the resection of the extradural as well as the intradural component by a complementary oblique corpectomy. There was no morbidity in relation to VA control as well as no postoperative instability.

Adult↗
PubMed1994

Neural sheath tumors of major nerves.

Over a 22-year period, operations were performed on 263 patients for 288 primary benign tumors of major peripheral nerves. The tumors included 85 schwannomas, 197 neurofibromas, and six plexiform neurofibromas. Total removal was achieved in 83 of the 85 schwannomas, and 76 of these patients were available for follow-up evaluation. Motor function either improved or was unchanged in 87% of these patients and 85% of those with pain in the distribution of the involved nerve had either total or partial resolution of their symptoms. Of the neurofibromas, 123 occurred in 121 patients without von Recklinghausen's disease. All tumors within this group were completely excised using a fascicular approach to the tumor. Of the 99 patients available for follow-up evaluation, 90% had either improved or unchanged motor function and 88% had partial or complete resolution of pain syndromes. Fifty-nine patients with von Recklinghausen's disease had 80 tumors removed: 74 fusiform tumors (58 of which were completely removed) and six plexiform tumors. Forty-eight of the 58 patients with gross total removal of fusiform tumors were available for follow-up evaluation, of whom 83% had improved or unchanged motor function and 74% had partial or complete resolution of pain syndromes. All six patients with plexiform tumors had progression of symptoms postoperatively. One brachial plexus schwannoma recurred and was re-excised without subsequent recurrence at the 5-year follow-up evaluation. Several incompletely excised plexiform neurofibromas have recurred with a symptomatic presentation.

Adult↗
PubMed1997

MR imaging differentiation of benign and malignant peripheral nerve sheath tumors: use of the target sign.

BACKGROUND: T2-weighted MR imaging of soft tissue tumors of neural origin may show round lesions with a central hypointensity and a hyperintense rim resembling a target. We define the "target sign" as a mass consisting of a solitary target, or a multicompartmental mass in which the largest component consists of multiple targets. OBJECTIVE: The objective of this study was to determine whether the target sign can differentiate benign neurofibromas and their malignant counterparts, malignant peripheral nerve sheath tumors. Materials and methods. Preoperative T2-weighted MR images of 23 neurofibromas or malignant peripheral nerve sheath tumors were retrospectively reviewed in 16 patients, aged 3 weeks to 20 years (median 15 years), without knowledge of the pathologic diagnosis. The presence or absence of a target sign was noted. RESULTS: The target sign was seen in all 12 neurofibromas and 1 of the 11 malignant peripheral nerve sheath tumors. Statistical analysis showed good differentiation of benign and malignant tumors using this sign (chi = 0.91). CONCLUSION: The target sign on T2-weighted MR imaging is helpful in differentiating neurofibromas from malignant peripheral nerve sheath tumors.

Adolescent↗
PubMed2006

Nf1 haploinsufficiency augments angiogenesis.

Mutations in the NF1 tumor-suppressor gene underlie neurofibromatosis type 1 (NF1), in which patients are predisposed to certain tumors such as neurofibromas and may associate with vascular disorder. Plexiform neurofibromas are slow growing benign tumors that are highly vascular and can progress to malignancy. The development of neurofibromas requires loss of both Nf1 alleles in Schwann cells destined to become neoplastic and may be exacerbated by Nf1 heterozygosity in other non-neoplastic cells. This study tested the hypothesis that Nf1 heterozygosity exaggerates angiogenesis. We found that Nf1 heterozygous mice showed increased neovascularization in both the retina and cornea in response to hypoxia and bFGF, respectively, compared to their wild-type littermates. The increase in corneal neovascularization was associated with heightened endothelial cell proliferation and migration, and increased infiltration of inflammatory cells. In addition, Nf1 heterozygous endothelial cell cultures showed an exaggerated proliferative response to angiogenic factors, particularly to bFGF. These findings support the conclusion that Nf1 heterozygosity in endothelial cells and perhaps inflammatory cells augments angiogenesis, which may promote neurofibroma formation in NF1.

Animals↗